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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Charles Trey, MD Memorial Postdoctoral Research Fellowship
Columbia University, New York, New York
Analysis of cell-specific TGFß effects in hepatic fibrogenesis and carcinogenesis
The TGFβ signaling pathway plays a crucial role in the activation of hepatic myofibroblast and the promotion of liver fibrosis. Moreover, it is known that TGFβ signaling affects tumor development in many organs including the liver as demonstrated by profound changes in TGFβ signaling in a large percentage of hepatocellular carcinomas (HCC). While the development of hepatic fibrosis is associated with increased TGFβ signaling, the development of HCC is associated with decreased TGFβ signaling.
Dr. Pradere’s previous studies show a strong downregulation of the TGFβ-antagonistic pseudoreceptor BAMBI during hepatic stellate cell activation whereas BAMBI is upregulated in HCC suggesting a different regulation of TGFβ signaling in different cellular compartments during chronic liver injury. Notably, normal hepatocytes are highly responsive to TGFβ and may undergo cell death in response to TGFβ but the role of hepatocytes TGFβ signaling in chronic hepatic injury and HCC is not well understood. Dr. Pradere hypothesizes that the seemingly opposite roles of TGFβ in fibrosis and cancer are related to different TGFβ signaling status at different time points and in different cellular compartments: In early stages of chronic injury, increased TGFβ signaling in hepatic myofibroblasts and potentially also hepatocytes promotes the development of fibrosis and creates a fibrotic microenvironment that may provide a fertile “soil” for the development HCC. At later stages, loss of TGFβ signaling in the epithelial compartment unleashes the TGFβ-mediated growth inhibition and death of hepatocytes, and thereby promotes the survival and proliferation of the malignant “seed”. Aims: To demonstrate how deletion of TGFβ pseudoreceptor BAMBI affects fibrosis and hepatocarcinogenesis (Aim1). To determine how inactivation of TGFβ signaling in hepatocytes affects hepatic fibrosis and carcinogenesis (Aim 2). Methods and Research Plan: He will analyze the contribution of BAMBI to fibrogenesis and carcinogenesis by subjecting mice with global BAMBI deletion to bile duct ligation, CCl4 treatment and chemical hepatocarcinogenesis. Dr. Pradere generated mice with hepatocyte-specific deletion of TGFβ receptor (TBR) 2 and will evaluate fibrogenesis and carcinogenesis after bile duct ligation, CCl4 treatment and chemical hepatocarcinogenesis. Preliminary and anticipated results: Dr. Pradere’s preliminary data shows decreased injury and fibrogenesis after BDL in mice with hepatocyte-specific deletion of TBR2 suggesting that epithelial TGFβ signaling plays a role in early stages of chronic injury. It is anticipated that mice with global BAMBI deficiency display increased fibrosis after BDL, and that hepatocyte-specific deletion of TBR2 or deletion of BAMBI will promote DEN-induced hepatocarcinogenesis.
These results would suggest that cell-specific targeting of the TGFβ pathway is necessary for the treatment of liver fibrosis to prevent tumor-promoting effects of TGFβ inhibition in the epithelial compartment.